The main goal of this revision (competitive supplement) is to study whether treatment with valacyclovir is associated with less tau accumulation in the brain compared to patients treated with placebo in our VALAD (Valacyclovir for Alzheimer?s Disease) trial funded by NIA (R01AG055422). This will be determined by tau positron emission tomography (PET) using the ligand 18F-MK-6240 at baseline and 78 weeks in 130 patients with mild Alzheimer?s disease (valacyclovir n=65, placebo n=65). An additional goal is to add baseline CSF studies of A?, tau and phospho-tau181 to CSF studies already planned to be done at 12 and 78 weeks. After the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can later enter the brain via retrograde axonal transport, often targeting the temporal lobes. HSV1 can also enter the brain via olfactory neurons directly. HSV1 (oral herpes) and HSV2 (genital herpes) trigger amyloid aggregation and their DNA is commonly found in amyloid plaques. Anti-HSV drugs reduce both A? and p-tau accumulation in infected mouse brains. HSV1 reactivation is associated with tau hyperphosphorylation in mice and may play a role in tau propagation across neurons. In humans, recurrent reactivation with newly produced HSV1 particles, ?drop by drop,? may produce neuronal damage and eventually lead to neurodegeneration and Alzheimer?s disease (AD) pathology. Clinical studies show cognitive impairment in HSV seropositive patients in different patient groups and in healthy adults. We will conduct the first-ever clinical trial to address the long- standing viral etiology hypothesis of AD which posits that viruses, particularly the very common HSV1 and HSV2, may be etiologic or contribute to the pathology of AD. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral doses of 2 to 4 g per day to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) in a randomized, double-blind, 78-week Phase II proof of concept trial. Patients treated with valacyclovir are hypothesized to show smaller decline in cognition and functioning compared to placebo, and, using 18F-Florbetapir PET imaging, to show less amyloid accumulation than placebo over the 78- week trial, and, using 18F-MK-6240 imaging, to show less tau accumulation than placebo during the trial. Apolipoprotein E genotype at baseline, changes in cortical thinning on MRI, olfactory identification deficits, and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed to establish the degree of CNS penetration of valacyclovir in mild AD, and we will obtain CSF A?42, tau, p-tau for exploratory analyses with changes in outcome measures. If this trial is successful, we will apply for funding to conduct a larger Phase III study using a study design that will be informed by the results of this Phase II trial. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of AD.